Progressive cognitive dysfunction and ultimately death in Alzheimer's disease (AD) result from degeneration of nerve cell circuits in the brain. This project tests the hypothesis that synapses are the sites where the neurodegenerative process begins. Specifically, we will elucidate the biochemical cascades that result in synaptic dysfunction and degeneration in AD in well-characterized animal and cell culture models. Specifically, we will elucidate the biochemical cascades that result in synaptic dysfunction in AD in well-characterized animal and cell culture models. Specific aim 1 will test the hypothesis that apoptosis-related biochemical events involving oxidative stress, PAR-4 induction, caspase activation and mitochondrial dysfunction occur locally in synaptic compartments in vitro (synaptosomes and primary hippocampal neurons), and in vivo in presenilin-1 mutant knockin mice following insults relevant to AD. Specific aim 2 will test the hypothesis that oxidative stress and increased Par-4 production occur locally in synapses in AD. This will be accomplished using confocal microscope analysis of brain sections, and biochemical analysis of synaptosomes prepared from rapid autopsy brain tissues from AD and control patients. Specific aim 3 will test the hypothesis that PA-4 production and caspase activation are critical links in the chain of events that leads to synaptic degeneration and neuron death in AD. This will be accomplished using antisense and pharmacological approaches. Specific aim 4 will test the hypothesis that activation of neurotrophic factor signaling pathways will increase resistance. of synaptic terminals to dysfunction and degeneration. Based upon preliminary data suggesting that certain neurotrophic factors can exert protective effects in synaptic terminals, we will determine whether the trophic factors suppress apoptotic cascades. This research will provide novel insight into molecular and biochemical events occurring locally in synaptic compartments in AD that are likely to determine the extent of degeneration of neuronal circuits; and associated behavioral deficits. We will identify molecular targets for development of therapeutic agents aimed at reducing the extent of brain injury and improving outcome in AD patients.